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The Big Picture for Genfit : NASH patients with

Diabetes and Cardiovascular Risk


Since the publication of the preliminary results of Genfit's phase IIB clinical trial of GFT505 (now
Elafibranor) in March 2015, many observers have been focused on certain details of the liver biopsy
results, especially the positive reversion of patients with low NASH scores in the placebo group
which biased the overall results. By focusing on these details, observers, investors and especially
analysts are failing to see the Big Picture. This may well be deliberate on the part of some analysts
who favour, or have interests in the US company Intercept, also in the race to treat NASH. These
biopsy results for low NASH patients are misleading due to their low accuracy and are a diversion
that hides the Big Picture for NASH patients.

1) Put aside Misleading Details:


Biopsy data from low NASH patients is inaccurate and misleading
Several publications have demonstrated that biopsy data is inaccurate because of to sampling
variation. A typical biopsy represents 1/50 000 of the volume of the liver and NASH varies
depending on the sampling site. A study designed to measure sampling variations by taking two
biopsies from the same patient, carried out by V Ratziu et al, one of the leading experts on NASH,
Sampling variability of liver biopsy in nonalcoholic fatty liver disease demonstrated a
discordance of one stage or more for 41% of patients. Ballooning discordance was 24%
between the two biopsies.
Since 41% of biopsies may be in error by at least one NASH stage due to sampling variation, it is
not surprising that many low-NASH patients treated with placebo were recorded as cured when
second biopsies were taken at the end of the Genfit trial. This result is in total discordance with the
blood tests of cured patients, which showed that they were still at high risk of diabetes and CVD
events. More on the misleading impact of histological variation can be found here or in the article
New Genfit data challenge placebo positives This subject is also discussed in the excellent
article by Rosana Kapella, Setting The Pace In The Race To Treat NASH

2) Look at the Big Picture:


NASH patients have Diabetes and Cardiovascular Risk
The Big Picture is that most NASH patients need an effective global treatment not only for NASH,
but also for insulin resistance, diabetes and cardiovascular risk and that Elafibranor is effective in
treating all of these conditions.
It is well established that most NASH patients are pre-diabetic or diabetic (resistant to insulin) and
dyslipidemic (unhealthy levels of lipids and triglycerides in the blood). These diseases are part of
the Metabolic Syndrome and often occur together. Indeed most NASH patients are at much higher
risk of dying from complications of diabetes or from heart disease and stroke than they are from
NASH alone. 38% of NASH patients die from CVD (heart disease and stroke). CVD is the biggest
killer in the US, with 85 million patients and 15% of deaths from all causes.

Metabolic Syndrome Risk Factors


The US National Heart Institute defines the Metabolic Syndrome as a group of risk factors that
raises your risk for heart disease and other health problems, such as diabetes and stroke.
The conditions described below are metabolic risk factors. These risk factors tend to occur together.
You must have at least three metabolic risk factors to be diagnosed with metabolic syndrome.
Obesity. Excess fat in the stomach area is a greater risk factor for heart disease than excess
fat in other parts of the body, such as on the hips.
A high triglyceride level (or you're on medicine to treat high triglycerides). Triglycerides are
a type of fat found in the blood.
A low level of HDL cholesterol (or you're on medicine to treat low HDL cholesterol). HDL
sometimes is called "good" cholesterol. This is because it helps remove cholesterol from
your arteries. A low level of HDL cholesterol raises your risk for heart disease.
High fasting blood sugar (or you're on medicine to treat high blood sugar). Mildly high
blood sugar may be an early sign of diabetes. Insulin resistance also may increase your risk
for metabolic syndrome. Insulin resistance is a condition in which the body cant use its
insulin properly.
Most NASH patients have all of the above risk factors. Indeed NASH is recognised as being
caused by excessive levels of triglycerides in the blood which leads to excessive fat storage in the
liver. NASH patients therefore need to be protected from all the factors of Metabolic syndrome as
well as from NASH.
Elafibranor works by stimulating improved fat and sugar management
Elafibranor stimulates the nuclear receptors PPAR alpha and delta. These are the operators that
control the transformation and storage of sugars and lipids in the blood, liver, fat storage cells and
muscles. You can find an explanation of the Mechanism of PPARs here . By stimulating better fat
and sugar management, Elafibranor acts to correct the causes of both NASH and Metabolic
Syndrome. The results taken from the latest phase IIB clinical trial are clear on this.

3) Analyse the Impact of the Big Picture:


Elafibranor improves NASH + CVD risk + Insulin Resistance
For Cardiovascular Diseases
- Elafibranor significantly reduces plasma triglyceride levels
- Elafibranor significantly reduces Total and LDL (bad) Cholesterol and increases HDL
(good) Cholesterol

For Insulin Resistance and Diabetes


- Elafibranor significantly reduces fasting plasma glucose levels
- Elafibranor significantly reduces HOMA-IR insulin resistance
For NASH
- Elafibranor significantly reduces markers of liver diseases : ALT, ALP, gGT
- Elafibranor significantly reduces histological NASH scores
- Elafibranor significantly reduces markers of fibrosis
- Elafibranor significantly reduces markers of inflammation

Conclusion : Elafibranor will be strongly recommended by doctors for all NASH and NAFLD
patients since they are all potentially at risk from diabetes and CVD.
In comparison, Intercept's OCA increases both cardiovascular risks and insulin resistance
which makes it counter-indicated for most NASH patients. This is the result of its mechanism
of action (The-Paradox-of-Obeticholic-Acid-for-the-Treatment-of-NASH)

Where can you check out this information ?


Much of this information can be found in a poster displayed at the AASLD conference in
November 2015, signed by 17 authors from 14 different institutions and presented for discussion by
the leading experts in liver diseases. This poster gives information on Nash Patients treated with
Elafibranor or with placebo during Genfit's phase IIB trial. The results compare histological NASH
scores with results for liver enzymes, plasma lipids (triglycerides and cholesterol), plasma sugars,
insulin sensitivity and other markers.
More information can also be found in Genfit's AASLD Investor presentation

Albert Wright PhD,


Revised 16 December 2015